Controlled Viscosity Tissue Adhesive

ABSTRACT

Disclosed are methods and compositions for closing and sealing a wound, laceration, incision, or other percutaneous opening using an adhesive. In one preferred embodiment, the sides of the percutaneous opening are brought together in apposition and the adhesive is applied topically over the apposed opening and the skin adjacent thereto. Adhesives used in the methods of the preferred embodiments exhibit sufficient viscosity to substantially prevent flow of the adhesive into the percutaneous opening. Adhesives may also be used in surgical applications, as a covering for a trauma to the outer surface of the skin, or as a secondary means of closure in combination with other means of closure, including staples and sutures. In a preferred embodiment, the adhesive is a adhesive comprising cyanoacrylate monomer, cyanoacrylate polymer, and a plasticizer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 10/968,464, filedOct. 19, 2004, which is a continuation-in-part of application Ser. No.10/145,581, filed May 13, 2002, which is a continuation of applicationSer. No. 09/702,013, filed Oct. 13, 2000, which is a continuation ofapplication Ser. No. 09/339,146, filed Jun. 24, 1999, now U.S. Pat. No.6,155,265, issued Dec. 5, 2000, which is a continuation-in-part ofapplication Ser. No. 09/078,944, filed May 14, 1998, now abandoned,which is a continuation-in-part of application Ser. No. 08/991,823 filedDec. 17, 1997, now abandoned, and also claims priority to U.S.Provisional Application Ser. No. 60/602,975, filed Aug. 19, 2004, thedisclosures of each of which are incorporated by reference herein intheir entireties.

BACKGROUND OF THE INVENTION

The present invention relates to medical and surgical tissue adhesives.In one embodiment, the adhesive is of the type useful for bondingadjacent sections of skin separated by percutaneous incision ortraumatic injury.

DESCRIPTION OF THE RELATED ART

Every year, over 10 million traumatic wounds are treated by emergencyphysicians in the United States. A great many incisions ranging from afew millimeters to several centimeters in length are closed each year bymedical personnel. Countless more less serious wounds are treated bynon-medical persons, such as athletic trainers, parents of an injuredchild, or the injured individual himself.

Small wounds and lacerations can be treated by simply bandaging thewound or by using tape to keep the edges of the wound in apposition.Such methods can be performed with a minimum of time and training, aswell as causing little or no additional trauma to the wound or causingthe patient additional pain.

More serious wounds or incisions are generally treated by conventionalmethods, such as suturing. Suturing requires the use of a needle andoften involves a local anesthetic. Suturing can be costly because it istime-intensive and the procedure requires that the individual performingit have some medical training. Additionally, suturing can be painful andthe use of needles may cause further distress for an already traumatizedpatient, as well as expose medical personnel to potential needlestickinjury. Furthermore, because most sutures used topically do notdissolve, the patient generally must make a return visit at a later datefor the often uncomfortable procedure of removal of the sutures.

In recent years, cyanoacrylate tissue adhesives have been tried as analternative for such conventional methods. The most commonly usedcyanoacrylates for wound closure include octyl- and butylcyanoacrylate,have some advantages over suturing, such as faster and less painfulclosure. These monomers like all cyanoacrylate monomers have severaldrawbacks. One drawback is that they have a very low viscosity. The lowviscosity makes precise application difficult, in that the adhesiveflows over areas of the skin surface well beyond the immediate region ofthe closure and that the adhesive is readily drawn into the wound,effectively creating a barrier between the two tissue surfaces which aredesirably rejoined in the natural healing process thereby blockingepithelealization and fibroblast growth. Furthermore, certaincyanoacrylate monomers and formulations form a closure which is hard,brittle, and inflexible, and which sets up too quickly to allow foradjustment of the opposing skin surfaces following its application.

SUMMARY OF THE INVENTION

There remains a need for a simple and effective method and compositionfor effecting wound closure. Preferably, the method and composition canbe utilized with minimal training time and risk of error, and will notmaterially increase complications, immunogenicity, scarring, infection,or other negative factors.

In accordance with one aspect, there is provided a tissue adhesive. Thetissue adhesive comprises about 1-15% by volume cyanoacrylate polymer;about 2-15% by volume plasticizer and about 70-95% by volume of amixture of first and second cyanoacrylate monomers, each having thegeneral formula (I):

wherein R is alkyl and the first cyanoacrylate monomer has at leastabout 3 carbon atoms and the second cyanoacrylate monomer has no morethan about 10 carbon atoms.

In accordance with another of the preferred embodiments, there isprovided a method of closing a percutaneous opening, having a firstdermal surface on a first side of the opening and a second dermalsurface on a second side of the opening and generally coplanar with thefirst dermal surface. The method comprises applying an adhesive layeracross at least a portion of the first and second dermal surfaces andspanning the opening, wherein the adhesive comprises a blendedcyanoacrylate monomer, cyanoacrylate polymer and plasticizer; andexhibits a sufficient viscosity to substantially prevent flow of theadhesive into the opening.

In accordance with another preferred embodiment, there is provided amethod of closing and sealing a joint formed between a tissue of apatient and a second surface, comprising positioning a tissue of apatient adjacent to a second surface; securing the tissue to the secondsurface using a primary closure modality to form a joint; delivering anadhesive comprising cyanoacrylate monomer, cyanoacrylate polymer, and aplasticizer to the joint; and permitting the adhesive to polymerize.

In accordance with a further embodiment, there is provided a method ofclosing and sealing a wound in a patient. The method comprises the stepsof identifying a percutaneous wound having first and second sides,delivering a layer of wound closure adhesive comprising cyanoacrylatemonomer, cyanoacrylate polymer, and a plasticizer to the surface ofskin, blood vessel or other tissue on each of the first and second sidesand across the wound in a quantity sufficient to retain closure andsealing of said would, and restraining the adhesive from entering thewound.

In accordance with a further embodiment, there is provided a method ofcovering a trauma to an outer layer of a skin in a patient. The methodcomprises delivering an adhesive comprising cyanoacrylate monomer,cyanoacrylate polymer, and a plasticizer to a surface of the skinspanning an area of the trauma to the outer layer of the skin in aquantity sufficient to cover said trauma; and permitting the adhesive topolymerize.

Further features and advantages of the present invention will becomeapparent to those of skill in the art in view of the detaileddescription of preferred embodiments which follows, when consideredtogether with the attached drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-section of a rollerball container-applicator as can beused to apply adhesives in accordance with the preferred embodiments.

FIG. 2 depicts the use of a rollerball container-applicator of the typein FIG. 1 to deliver adhesive to a topical wound to effect closure inaccordance with the preferred embodiments.

FIG. 3 is a view of an alternate container-applicator for use inaccordance with the preferred embodiments.

FIG. 4 is a cross-section of the container-applicator of FIG. 3.

FIG. 5 is a blown-up view of the applicator tip of thecontainer-applicator of FIG. 3 showing the placement of a break-awaysealing tip.

FIG. 6 is a cross-section of a percutaneous opening or wound which hasbeen closed and sealed according to the preferred embodiments.

FIG. 7 is a view of a tube container-applicator for use in accordancewith the preferred embodiments.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Several considerations come into play when a closing percutaneousopening, such as a wound or incision. The considerations includeproviding a closure having adequate strength to resist opening orrupture and providing a closure which protects the opening, but does notat the same time substantially interfere with the normal healingprocesses. One method that can be used is the application of anadhesive. An adhesive can be used either with or without additionalclosure means.

When the adhesive used is a liquid, it presents a different set ofconsiderations as compared to solid materials and other conventionalmethods of closure, such as staples, sutures, and bandages. Several ofthese considerations have to do with the viscosity of the adhesive.

In discussing the viscosity of the adhesives in the context of preferredembodiments, the viscosity referred to herein is the viscosity of theadhesive at the time it is being applied. Following application, theadhesive will increase in viscosity until the adhesive “sets up” to formthe final solid or relatively solid state of the adhesive closure due tophysical or chemical mechanisms in the adhesive or adhesive preparation,including, but not limited to, curing, cross-linking, polymerizing, andevaporation of solvent. Once the adhesive has set up to form theclosure, it will preferably take a solid form, which can be flexible,rubbery or stiff, with firm but flexible closures being preferred.Furthermore, unless specifically referenced otherwise, all percentagesherein are percentages by volume.

Adhesives used in accordance with preferred embodiments preferably havea viscosity low enough such that they flow (and can be spread) whenacted upon by gravity or some other force, such as being squeezed out ofa tube or spread with an applicator. This action allows for the adhesiveto wet the skin adjacent the opening and also allows for application ofthe adhesive by a variety of methods. On the other hand, the viscosityof the adhesive during application is preferably not so low that theadhesive becomes runny and flows far beyond the general vicinity of theintended application surface or that it flows into the opening itself.This is an especially important consideration, because if the adhesiveflows a substantial distance into the opening, it can block the surfacesthat are to be healed together, and thus can actually impede or preventthe healing process by acting as a barrier to the migration of basalcells and collagen in the natural healing of a wound. Seepage into thewound is a significant problem with adhesives known in the art, such asliquid cyanoacrylates which have a very low viscosity and will, whenplaced on a wound, run into the wound or be drawn therein via capillaryaction. Accordingly, a preferred adhesive polymerizes and sets before itruns into a wound, incision, opening, or into undesired areas. Anexample of a preferred situation of applying an adhesive is applying alayer of the adhesive to a horizontal wound plane and then moving thewound plane to a vertical position and allowing the adhesive topolymerize without running.

To achieve at least some of the properties discussed above, the adhesiveused to close a percutaneous opening in accordance with the preferredembodiments preferably has sufficient viscosity, realizing that“sufficient viscosity” is a combination of the volume and mass ofmaterial used as well as the setting times of the adhesive used toachieve the purpose. In general this is a viscosity greater than about100 centipoise, but may be as low as 50 cps if initiators oraccelerators are use to speed the rate of curing so that the adhesivesets before flowing into unwanted areas. Although very high viscositymaterials can be used in accordance with the preferred embodiments,viscosities of less than about 100,000 are generally used, and it ispreferred that the viscosity be less than about 5,000 centipoise, orless than about 2500 cp such that the adhesive maintains a reasonableamount of workability and ability to flow under pressure. In a preferredembodiment, the viscosity of the adhesive is within the range of fromabout 100 to about 10,000 centipoise, including about 200 cp, 300 cp,400 cp, 500 cp, 600 cp, 700 cp, 800 cp, 900 cp, 1000 cp, 2000 cp, 3000cp, 4000 cp, 5000 cp, and 7500 cp. Ranges of viscosities which comprisethe preceding viscosities and those between the recited viscosities andare limited at their high and low ends by any two of the recitedviscosities are also contemplated (e.g. 300-700 cp, 400-900 cp, etc.).

Adhesives according to preferred embodiments preferably comprisecyanoacrylates. Cyanoacrylates have the general formula as shown below.As also shown below, cyanoacrylates can polymerize to polycyanoacrylatesin the presence of water from the air or trace amounts of moisture onthe surface to which the adhesive is being applied. Upon application tothe surface, the monomer undergoes an exothermic hydroxylation reactionthat results in polymerization.

In the formula above, R may be any organic group which does notinterfere with the polymerization of the monomer to form thepolycyanoacrylate. In a preferred embodiment, R is alkyl which includesstraight-chain, branched, and cyclic groups, and include from about 2 toabout 12 carbon atoms, more preferably from about 3 to about 10 carbonatoms.

A cyanoacrylate can been modified to increase its viscosity and/ordecrease its polymerization rate. The viscosity of the cyanoacrylate canbe increased to a gel or paste form by chemical modification of thecyanoacrylate molecule and/or by the presence of one or moreviscosifying agents.

Examples of compounds used in connection with certain embodimentsinclude polymerizable cyanoacrylates that have been cross-linked orco-polymerized with other compounds that can alter elasticity, modifyviscosity, aid biodegradation or change some other property of theresulting material. For example, polyacrylic acid having a molecularweight of 200,000 to 600,000 can be cross-linked to a cyanoacrylate toform compounds that allow the absorbability to be coordinated with thetissue regeneration rate and can feature higher elasticity thancyanoacrylates alone. Absorbability is generally unnecessary for topicalapplications, with the adhesive film simply falling off in a few days.

In a preferred embodiment, the adhesive comprises the followingcomponents: 1) cyanoacrylate monomer, 2) cyanoacrylate polymer, and 3)plasticizer. The cyanoacrylate monomer gives adhesive properties. In thechoice of a cyanoacrylate monomer for adhesiveness, factors to beconsidered include rate of polymerization, tensile strength, andbrittleness and flexibility. These factors are also balanced with thechoice of the other ingredients, the cyanoacrylate polymer andplasticizer. The cyanoacrylate polymer which, having a high molecularweight, is used as a viscosifying agent and adds flexibility. Thecyanoacrylate polymer also gives tensile strength. The plasticizerenhances flexibility and resilience. Additionally, to the formulationsof the preferred embodiments, any of a variety of other additives canalso be added, such as bacteriostatic agents, anti-inflammatory agents,and preservatives, stabilizers and the like, as will be understood bythose of skill in the art. In some embodiments, formulations of tissueadhesives can additionally comprise one or more optional additives, suchas polymers, viscosity modifiers, colorants, perfumes, anti-diffusionagents, salts, antibiotics, anti-microbials, stabilizers, desiccants,catalysts, or agents that alter polymerization rate.

Among the reasons that cyanoacrylates are preferred for use in tissueadhesives are their several particular advantages as an adhesivecompound. First, they can harden almost instantaneously on contact withsurfaces having moisture thereon. These contact areas include mosttissues and surfaces in and on the body of an animal, such as a human.Second, experiments by the inventor indicate that cyanoacrylate sealedvascular punctures can withstand several times the maximum potentialsystolic pressure, and hence, would not be expected to fail when used toseal most surface wounds. Cyanoacrylates are also naturallythrombogenic. This property is an advantage in certain applications asit promotes the first step in healing.

Preferred compounds to be used in the adhesives disclosed herein includeat least one of the biologically suitable monomer compounds within thecyanoacrylate family. The cyanoacrylate family includes methylcyanoacrylate, ethyl cyanoacrylate, n-propyl cyanoacrylate, isopropylcyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-amylcyanoacrylate, isoamyl cyanoacrylate, hexylcyanoacrylate,octylcyanoacrylate, 3-acetoxypropyl cyanoacrylate, 2-methoxypropylcyanoacrylate, 3-chloropropyl cyanoacrylate, benzyl cyanoacrylate,phenyl cyanoacrylate, alkenyl cyanoacrylate, butyl-2-cyanoacrylate,alkoxyalkyl 2-cyano acrylates, fluorinated 2-cyanoacrylates, andcarbalkoxyalkyl cyanoacrylates, depending upon acceptable toxicity andother properties for a given application. In a preferred embodiment, theadhesive compound comprises octylcyanoacrylate and butylcyanoacrylate.Other members of the cyanoacrylate family may be commercially availableor can be synthesized according to published procedures or analogousmethods as is within the abilities of one skilled in the art.

Among the preferred cyanoacrylate monomers are octylcyanoacrylate, inwhich R is octyl, and butylcyanoacrylate, in which R is butyl. Theproperties of the cyanoacrylate can be modified by altering the R groupof the alkoxycarbonyl group. The shorter-chain derivatives tend to havea higher degree of tissue toxicity than the longer-chain derivatives.However, the shorter-chain derivatives provide advantages as a dermaladhesive according to its properties. Shorter-chain derivatives providestronger bonds and more rapid curing. For example,polybutylcyanoacrylates are rigid when dry, but provide a strong bondand polyoctylcyanoacrylates are more flexible when dry, but produce aweaker bond. However, the shorter-chain derivatives provide advantagesas a dermal adhesive according to its properties. Shorter-chainderivatives provide stronger bonds and more rapid curing. For example,polybutylcyanoacrylates are rigid when dry, but provide a strong bondand polyoctylcyanoacrylates are more flexible when dry, but produce aweaker bond.

Inflammation, tissue necrosis, granulation formation, and woundbreakdown can occur when cyanoacrylates are implanted subcutaneously.The process causing the histological toxicity is thought to be relatedto a general foreign body reaction and the by-products of degradation,cyanoacetate and formaldehyde. The local concentrations of thesebreakdown products are proportional to the rate of degradation (anaqueous degradation process) of the parent compound. Therefore, slowerdegradation rate results in less toxicity to the tissues. Thisphenomenon is explained by the hypothetical possibility that slowlydegrading compounds release degradation products more gradually, therebypermitting more effective clearance and invoke a less intenseinflammatory response. The longer-chain compounds degrade much moreslowly than the shorter-chain compounds, hence the lower reactivity andtoxicity of the longer-chain compounds.

There is a wide variation in the rates and facility of in vivobiodegradation of polymers made from cyanoacrylate monomers which can beused as adhesive compounds in the preferred embodiments and this widevariation is contemplated. Generally, polymers of cyanoacrylates whichhave substituents that are small and/or contain one or moreoxygen-containing functional groups (e.g. ether, ester, carbonyl) appearto have increased biodegradability rates. Cyanoacrylates having longchain alkyl groups lacking in oxygen-containing functional groups assubstituents can tend to form polymers which biodegrade more slowly.There are also indications in the literature that the biodegradationrate of cyanoacrylate polymers is affected by the polymer molecularweight and crystallinity of the polymer.

There are several studies of biodegradation rates of polymers formed byvarious members of the cyanoacrylate family in the scientific andmedical literature. It is within the abilities of one of skill in theart to use such information in the literature along with routineexperimentation in order to choose a member of the cyanoacrylate familywith suitable biodegradation characteristics for use in accordance withthe preferred embodiments.

The above-listed members of the cyanoacrylate family, as well as othermembers of the cyanoacrylate family and other adhesive compounds thatfall within the scope of the preferred embodiments and are not listedabove, can differ in their properties when used in a adhesive. Theefficacy, histotoxicity, and other medically relevant properties ofabove-listed and other members of the cyanoacrylate family can bereadily determined by routine experimentation by one of ordinary skillin the art or by review of the medical literature. Such experimentationwill enable one skilled in the art to choose optimal cyanoacrylate orother adhesive compounds for use in the adhesive of the preferredembodiments for a desired specific application.

In preferred embodiments, cyanoacrylate polymer is used as aviscosifying agent. A long chain cyanoacrylate polymer can also aid inovercoming brittleness of the adhesive material. Also among theproperties that change with the quantity of cyanoacrylate polymer usedare viscosity and polymerization rate. Increasing the percentage ofcyanoacrylate polymer in the adhesive will increase the viscosity of theadhesive. Increased viscosity provides for easier application of theadhesive on tissues, as viscous adhesives stay where they are placed andthus decrease the incidence of running or dripping onto other surfacesor tissues, or leaking in between sides of an opening to be closed.Decreased polymerization rates allow more time for a practitioner toplace and adjust the surfaces that are to be sealed. Where thepolymerization time is short, there can be little if any margin forerror before the surfaces are sealed. The longer polymerization time hasan additional benefit. Since the polymerization process is exothermic,decreasing the polymerization rate decreases the rate that heat isreleased by the adhesive, resulting in a lower temperature in theadhesive and surrounding tissues during polymerization.

Preferred cyanoacrylate polymer compounds to be used in the viscosifyingagent of the preferred embodiments include a biologically suitablepolymer compounds made from at least one member within the cyanoacrylatefamily. As stated above, the cyanoacrylate family includes methylcyanoacrylate, ethyl cyanoacrylate, n-propyl cyanoacrylate, isopropylcyanoacrylate, n-butyl cyanoacrylate, isobutyl cyanoacrylate, n-amylcyanoacrylate, isoamyl cyanoacrylate, hexylcyanoacrylateoctylcyanoacrylate, decylcyanoacrylate, 3-acetoxypropyl cyanoacrylate,2-methoxypropyl cyanoacrylate, 3-chloropropyl cyanoacrylate, benzylcyanoacrylate, phenyl cyanoacrylate, alkenyl cyanoacrylate,butyl-2-cyanoacrylate, alkoxyalkyl 2-cyanoacrylates, fluorinated2-cyanoacrylates, and carbalkoxyalkyl cyanoacrylates, depending uponacceptable toxicity and other properties for a given application. Othermembers of the cyanoacrylate family may be suitable. to form thecyanoacrylate polymer for use as a viscosifying agent. Generallyspeaking, cyanoacrylate polymers having longer chain R groups arepreferred. Examples of cyanoacrylate polymers having a longer chain Rgroup are poly(octylcyanoacrylate) and poly(decylcyanoacrylate).

Another component in preferred embodiments of tissue adhesives is aplasticizer. Preferably, the plasticizer is suitable for use in themammalian body. Examples of suitable plasticizers include, but are notlimited to, tributyl citrate, acetyl tributyl citrate, dimethylsebacate, diethylsebacate, triethyl phosphate,tri(2-ethyl-hexyl)phosphate, tri(p-cresyl)phosphate, glyceryltriacetate, glyceryl tributyrate, dioctyl adipate, isopropyl myrisate,butyl sterate, lauric acid, trioctyl trimelliate, dioctyl glutatrate andmixtures thereof. Tributyl citrate is preferred.

In a preferred embodiment, the adhesive comprises about 70-95%cyanoacrylate monomer by volume, including 71%, 72%, 73%, 74%, 75%, 76%,77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, and 94%; about 2-15% cyanoacrylate polymer, includingabout 3%, 4%, 5%, 6%, 70%, 8%, 90%, 10%, 11%, 12%, 13%, and 14%; andabout 3-15% plasticizer, including about 4%, 5%, 60%, 7%, 8%, 9%, 10%,11%, 12%, 13%, and 14%. Ranges of percentages which comprise thepreceding percentages and those there between and are limited at theirhigh and low ends by any two of the recited percentages are alsocontemplated. For example, an adhesive may comprise about 80-90%cyanoacrylate monomer, about 3-10% cyanoacrylate polymer, and about5-10% plasticizer. In another embodiment, an adhesive comprises about84% cyanoacrylate monomer, about 8% cyanoacrylate polymer, and about 8%plasticizer.

In a preferred embodiment, the cyanoacrylate monomer component comprisesone or more cyanoacrylate monomer. By blending monomers, the propertiesof the adhesive can be modified. Cyanoacrylates with longer R groups cantake a longer time to polymerize; can have more flexibility; can haveslower degradation; and can have lower tensile strength. Also,cyanoacrylates with longer R groups often utilize initiators to set orcure. On the other hand, cyanoacrylates with shorter R groups can setvery quickly and release a significant amount of heat upon setting.Hence, cyanoacrylates with shorter R groups may utilize stabilizers tooffset the quick setting and significant heat release. Also, despitegreat tensile strength, cyanoacrylates with shorter R groups tend topolymerize to produce a brittle material and are prone to cracking andpremature sloughing when used topically on the skin. By combining acyanoacrylate with a longer R group with a cyanoacrylate with a shorterR group into blends, the properties of the resulting adhesive can bemodified. Although blends comprising one or more cyanoacrylates havinglonger R groups and one or more cyanoacrylates having shorter R groupsare preferred in some embodiments, blends may include only those havinglonger R groups or only those having shorter R groups.

One preferred cyanoacrylate monomer component composition comprisesoctylcyanoacrylate, as a cyanoacrylate with a longer R group, andbutylcyanoacrylate, as a cyanoacrylate with a shorter R group. Suchcompositions preferably comprise about 50% to about 95%octylcyanoacrylate and about 5% to about 50% butylcyanoacrylate,including compositions having the following ratios of octylcyanoacrylateto butylcyanoacrylate: 50:50, 55:45, 60:40, 65:45, 70:30, 75:25, 80:20,85:15, 90:10, and 95:5. Ranges of composition ratios which comprise thepreceding ratios and those there between and are limited at their highand low ends by any two of the recited ratios are also contemplated. Oneof ordinary skill of the art can optimize the properties of thecyanoacrylate monomer component by routine experimentation with theamounts of the members of the cyanoacrylate monomer component. In apreferred embodiment, mixtures having higher levels of cyanoacrylateshaving longer chain R groups further comprise an initiator to increasethe speed at which the adhesive sets up or cures. In the case ofoctylcyanoacrylate, use of an initiator is preferred in thoseembodiments having greater than about 80% octylcyanoacrylate.

In another embodiment, the cyanoacrylate monomer component comprises asingle cyanoacrylate monomer, with those having longer chain R groupsbeing preferred.

Depending upon the nature of the placement and composition of the twosurfaces to be joined, the degree of biodegradability orbioabsorbability desired in the adhesive employed can vary. For woundsor incisions on the surface of the skin, it can be acceptable to use aadhesive that is only slowly degradable or substantiallynonbiodegradable. For example, it is preferable that the adhesivematerial would slough off the surface of the skin in about 7 to about 10days. Alternatively, if both surfaces are living tissues which areinternal, it may be preferable to use an adhesive that will biodegradeover a period of days or weeks, diminishing as the natural healingmechanisms take hold.

If an adhesive having a chemical composition suitable for use in woundclosure does not have a viscosity in the preferred range, the preferredworking viscosity can be achieved in a variety of ways. If the desiredadhesive has a higher viscosity, such as can be found with a thick gelor rubber-like material, the adhesive can be combined with a solvent ofhigh or moderate volatility to lower the viscosity into the preferredrange. The solvent could then evaporate when it comes into contact withthe warm surface of the skin.

For thinner materials, which will likely form the great bulk ofdesirable adhesives, the viscosity should preferably be increased. If anadhesive sets up by means of polymerizing, cross-linking or other curingmechanism, a partially cured adhesive preparation can be used. By usinga partially cured adhesive, the viscosity could be brought within asuitable range for application according to the discussion herein. Suchan adhesive can be prepared by initiating the curing mechanism and thenquenching it, such as by adding an inhibitor. The curing mechanism wouldthen need to be re-initiated prior to application, or immediatelythereafter. This type of method could be used for UV-curable adhesives,for which re-initiation could begin by means of a W lamp or naturalsunlight once the adhesive is removed or expressed from its container.This method would also be suitable for adhesives which set up in thepresence of water, in that moisture in the air or on the skin couldprovide the needed water, or the site could be swabbed with water priorto application.

Although specific closure means and support structures are identifiedand discussed in this specification, such use of the terms should not beconstrued as limiting the definitions of these terms. It is theapplicant's intention that these terms be given their broad ordinarymeanings.

An adhesive according to preferred embodiments can be used to effectwound or percutaneous incision closure in a manner that is quick,simple, and effective. The preferred embodiments provide for a method ofclosing a percutaneous opening, having a first dermal surface on a firstside of the opening and a second dermal surface on a second side of theopening and generally coplanar with the first dermal surface. The methodcomprises a step of applying an adhesive layer across at least a portionof the first and second dermal surfaces and spanning the opening. Thematerials and methods of the preferred embodiments require littletraining for their use and can be used by medical personnel to replaceconventional methods of closing wounds. Additionally, they can be usedby non-medical persons for use in combination with or as a replacementfor conventional home remedies, such as adhesive bandages.

In accordance with preferred embodiments, an adhesive is used to joinadjacent surfaces of skin to effect closure of a wound or incision. Theadhesive used in accordance with the preferred embodiments are typicallyused as the primary closure modality, to replace sutures or staples. Thetwo sides to a percutaneous incision, for example, can be held togetherand a layer of adhesive can be placed on the surface to span theincision. After sufficient polymerization, the adhesive will provide astrong bond while natural healing processes occur under the surface. Itis preferred that the adhesives of the preferred embodiments are used asthe primary method of wound closure, but they can be used in conjunctionwith other wound closure or tissue fastening systems, such as staplesand sutures, or in combination with a support structure such as cloth orgauze.

Especially preferred adhesives are those which have a viscosity suchthat, when it is placed on the skin, the adhesive will span the gapbetween the two or more surfaces of the opening with no flow into theopening or without flowing a substantial distance into the opening. Theopening spanned without substantial seepage into the wound is generallyabout 0.1 mm to about 4 mm wide, preferably 0.5 mm to about 1.5 mm wide,and for many applications about 1 mm wide.

When adhesive is used having sufficient viscosity to span an opening asdescribed above, the adhesive can be made to form a thicker layer abovethe wound than would be possible with a thinner adhesive. This isbecause the more viscous adhesive will have a greater resistance to flowunder its own weight and will thus be more likely to stay in a shapeclosely approximating that in which it was applied. In one preferredembodiment, the adhesive, when applied to the skin, has the profile seenin FIG. 6. Such a profile can be achieved by using an applicator such asthat shown in FIGS. 3 and 4 or by applying a generally rounded bead ofadhesive to the skin which then wets the skin surface. This profile ofadhesive on the skin, wherein the layer of adhesive 18 forming theclosure is relatively thicker in the area generally over the opening 20between the pieces of skin 19, has advantages in that a thicker layer ofa given adhesive will have greater tensile strength than will a thinnerlayer of the adhesive. The increase in tensile strength of the materialforming the closure will provide increased protection against tearing orrupture of the opening following sealing.

In addition to the foregoing, the adhesive materials may be used as asecondary closure modality, being used in combination with sutures,staples, and other such primary closures. In such methods, the adhesiveis applied to the surface of the wound or incision, preferably after thewound is closed using the chosen primary closure means. The use of anadhesive further strengthens the closure and can also seal and protectthe closure area.

The adhesive material according to the preferred embodiments can also beused as a dressing to cover any trauma to the outer layer of the skin.Trauma to the outer layer of skin includes, but is not limited to,abrasions, scrapes, burns, blisters, bedsores, ulcers, chapping, andchafing, The adhesive material is delivered to a surface of the skincovering an area of the trauma to the outer layer of the skin in aquantity sufficient to substantially cover the trauma, or some portionthereof, and then is permitted to polymerize or cure allowing healingunderneath the polymerized material.

In addition to using the adhesive material for closure and sealing ofwounds and as coverings for trauma to the outer layer of the skin, theadhesive material may also be used as a surgical adhesive to bindtissues within the body to other tissues or materials. In such methods,a first surface and second surface are joined using the adhesivematerial. A first surface to be joined may be a surface of tissue in thepatient, and the second surface to be joined may be an autologous tissuefrom elsewhere in the same patient such as a harvested vessel, allographtissue such as a human transplant organ from a separate donor, animaltissue such as porcine or bovine heart valves, which may have beenpretreated in accordance with known technology, or any of a wide varietyof nontissue materials. Nontissue materials suitable for use with thepreferred embodiments include any of a variety of biologicallycompatible metals such as stainless steel, gold, platinum, or otherswell known in the medical device industry. The second surface may alsobe any of a wide variety of polymeric materials, includingpolyethylenes, polypropylenes, nylons, polytetrafluoroethylene and otherpolyfluoro compounds, polyesters such as Dacron, and other polymericmaterials known in the art. The second surface may also be a surface onany of a wide variety of implantable prostheses, prosthetic devices,grafts or organs. For example, the adhesive material may be useful inheart transplant, kidney transplant, liver transplant, lung transplantor other transplant procedures. In addition, a wide variety of vasculargrafting procedures can benefit from the use of adhesives according topreferred embodiments, including tissue grafts using vessels harvestedfrom elsewhere in the patient's body, as well as prosthetic grafts ofthe type which may be made from PTFE, Dacron, or other materials, eitheralone or in combination with supporting metallic cages. In addition, theadhesives may be used in connection with the implantation of replacementheart valves which will be subject to arterial pressure. Such valves mayinclude mechanical valves, bioprosthetic valves, and human allografts.Although specific prostheses, prosthetic devices, grafts and organs arenamed and discussed herein, such use of the terms should not beconstrued as limiting the definitions of these terms. It is theapplicant's intention that these terms be given their broad ordinarymeanings. Additionally, the terms device, graft, prosthesis and organshould be interpreted as including any skirts, supports, coverings oradditional materials attached to or associated with the device, graft,prosthesis or organ.

In addition to the foregoing, the adhesive material may also be used forskin, cartilage and bone grafting, sealing cerebrospinal fluid leaks,Tympanoplasty, ossiculoplasty, sealing bowel and vascular anastomosis,sealant for fractured teeth, and dressing for Aphthous ulcers.

The surgical method proceeds by bringing together the two surfaces thatwill form the joint and initially securing them together by a primaryclosure, including, but not limited to, those formed by the use ofsutures, staples, or other materials and methods known in the art. Thejoint between the two surfaces is then sealed and further secured byapplying the adhesive to the interface of the two surfaces. The methodof application may, in part, be determined by factors such as thecharacteristics of the chosen adhesive and the geometry, size andplacement of the application site. If required, the two surfaces areheld together by use of a suitable surgical instrument for the timerequired for polymerization of the adhesive.

Alternatively, the two (or more) surfaces may be brought together byclamps, forceps, hands or other removable means and secured and sealedby means of the adhesive alone, with the adhesive being applied in aquantity sufficient to retain closure or attachment of the surfaces. Theadhesive may be applied to one or both surfaces, either before or afterthe surfaces are brought together. After polymerization to the point ofadhesion, the clamps, forceps or the like are then removed such that theadhesive is the primary or even the only securing modality.

In other methods, the adhesive material is applied directly to a smallopening, such as a puncture, in a quantity sufficient to close and sealthe opening. In the case of a very small opening, the adhesive materialcan close the opening without any need for a separate step of bringingtogether two or more surfaces to be secured together.

Preferably, the adhesive material is allowed to dry, polymerize and/orcure following its application. The polymerization rate of the adhesivematerial should be such that the time to set the adhesive materialshould not be too short or too long and suitable for the clinicalindication. A short polymerization time would allow little if any marginfor error for sealing surfaces. A long polymerization time would notallow the convenience of a quick-sealing adhesive. Hence, a preferredset-up time for the adhesive material is about 10 to about 180 seconds,more preferably about 15 to about 90 seconds, including 20, 30, 40, 50and 60 seconds. The curing time is the time for the adhesive material toobtain maximal strength and completely dry and polymerize. In oneembodiment, preferred curing times for the adhesive material are about 1to about 5 minutes, including about 2, 3 and 4 minutes.

What follows is a discussion of several applicators and methods ofapplying the adhesives of the preferred embodiments. It is contemplatedthat any of the adhesives described herein can be used in connectionwith the devices and methods described as well as with other devices andmethods as will be apparent to those skilled in the art.

Any of a variety of containers, made of materials such as glass, plasticor aluminum, or devices can be used to apply or deliver adhesive to awound for closure and sealing. For example, syringes, eyedroppers,compressible bottles or tubes, tongue depressors, spatulas, and the likecan be used to deliver adhesive to the site intended for sealing.Adhesive can also be applied manually without the use of an applicator.Additionally, devices designed to deliver sealing adhesive can be used,such as that disclosed in U.S. Pat. No. 5,529,577. Once they areformulated, adhesives may be placed in container-applicators such asthose discussed in greater detail below. The choice of application ordelivery means can, in part, be determined by the viscosity of theadhesive employed. The choice of delivery means can also depend on otherfactors, such as the nature, physical structure, and location on thebody of the wound, incision or other opening to be closed and sealed.

Proper storage of tissue adhesives is an important consideration. Forexample, if a W-curing adhesive is used, the storage containerpreferably prevents penetration of UV radiation, and if a water-curingadhesive is used, a desiccant may be used. Because many cyanoacrylateswill polymerize and harden relatively rapidly when stored below acritical volume, it is preferable for the vessel or reservoir in whichthe adhesive is stored to contain more adhesive than is necessary toseal a typical site. Preferably, the storage vessel or reservoir in asingle-use container or container-applicator will contain a minimum ofabout 0.2 to about 5 grams of adhesive or more to maintain thecyanoacrylate monomer component in a generally unpolymerized state inthe storage vessel or reservoir prior to use. For multiple-usecontainers or container-applicators, the reservoir preferably containsabout 1 to about 10 grams, more preferably about 3 to about 5 grams ofadhesive. In certain embodiments, the volume of the container is halffilled to help maximize shelf life. The total volume of adhesive, thedesiccation measures, and the sealing structures in the container orcontainer-applicator can be optimized by one of skill in the art toprovide enhanced shelf life.

The tissue adhesives of the preferred embodiments are preferably storedand applied using a container-applicator. A container-applicator has twobasic parts: (1) a storage area or reservoir which holds the adhesiveand protects it from air, water and contaminants; and (2) the applicatorwhich comprises a specially shaped tip designed to aid in application ofadhesive.

The reservoir is preferably both air-tight and water-tight, and keepsthe adhesive within free from contaminants. The reservoir can contain adesiccant material to keep the adhesive free of water, which would causepolymerization of the preferred cyanoacrylate-based adhesive. Reservoirscan be of any shape, although shapes which provide for a smooth internalflow of adhesive, such as cylindrical or pyramidal shapes, arepreferred. The size of the reservoir can vary within a wide range, butis preferably slightly larger than the volume of adhesive which will beplaced inside the reservoir to minimize the amount of gas within thereservoir. The reservoir can be made from any of a variety of medicalgrade materials, such as plastics, that is suitable for the storage ofcyanoacrylates as is known in the art. The reservoir can be eitherrigid, collapsible, or compressible. Use of a compressible orcollapsible reservoir allows the user to have greater control over therate at which adhesive is expressed, as exertion of pressure on acompressible or collapsible reservoir would place a force on the on theadhesive causing it to flow at a faster rate than it would in theabsence of such pressure. The compressible or collapsible reservoirdesign is especially preferred for highly viscous or gel-like adhesivefor which the force of gravity may not be strong enough to cause a flowof adhesive through an applicator sufficient to close a wound.Collapsible reservoirs which retain their collapsed shape have theadditional advantage of reducing the amount of air which enters thereservoir following use. This advantage of collapsible containers is ofgreater importance in multiple-use (reusable) devices, wherein adhesiveis preferably kept relatively free of potential contaminants betweenuses.

Applicator tips can be of any of a number of shapes, sizes, andconfigurations. They are preferably fairly rigid and may be made out ofany material which is compatible with the adhesive formulation, and maybe plastic, cotton tipped swabs or high density foams, preferablyplastic. The choice of a proper applicator tip for a given applicationwill depend on factors such as the viscosity of the adhesive, thedesired application rate of the adhesive, the nature of the wound, theplacement of the wound on the body, and the physical structure of thewound.

The container-applicators of the preferred embodiments can be eithersingle-use or multiple-use devices. For most applications, single-usecontainer-applicator devices are preferred. This preference arisesbecause the risk of cross-contamination between wounds or patients ispractically eliminated when a new device is used for each closure. As analternative to the single-use embodiment, a container or reservoircontaining enough adhesive for multiple closures may be configured toaccommodate replaceable tips. In such an embodiment, at the placewhereon the replaceable tips connect with the reservoir, the reservoirwould preferably have a means such as a valve, septum or sealing gasketwhich allows the reservoir to be sealed in the absence of an applicatortip. Placing an applicator tip on the reservoir would cause the valve toopen, allowing adhesive to flow out from the reservoir. In this manner,one reservoir containing enough adhesive to close several wounds couldbe used over a period of hours, days or weeks. This embodiment wouldalso allow the user to use one reservoir with applicator tips of varyingshapes and sizes chosen to best accommodate the needs of differentwounds.

Three specific embodiments of container-applicators are depicted in thedrawings and detailed below.

One preferred embodiment of container-applicator is the rollerballcontainer-applicator 1 depicted in FIG. 1. The reservoir 2 can be eitherrigid, compressible, or collapsible and can be made out of any materialsuitable for the storage of cyanoacrylates, as is known in the art. Theapplicator tip portion of the container-applicator comprises a ball 3and a cuff 4. The ball 3 is held loosely within the cuff 4 so that theball 3 is free to rotate in any direction, but not so loosely as toallow the ball 3 to be removed or fall out when the container-applicator1 is inverted. The size of the gap 5 formed between the ball 3 and thecuff 4 can be varied to accommodate a wide range of viscosities ofadhesive and desired flow rates. For low viscosity adhesives, arelatively small gap 5 would be preferred to allow the adhesive to flowout around the ball at a reasonable rate during application, whereas forhigh viscosity gel-like adhesive a larger gap 5 would be required toallow a reasonable flow of adhesive around the ball 3. Similarly, thegap 5 can be varied to achieve a desired application rate for adhesivesof a particular viscosity. For adhesive of a given viscosity, a largegap 5 would provide a higher flow rate for the adhesive than a smallergap 5. Furthermore, use of a compressible or collapsible reservoir 2allows for additional control over the rate at which adhesive isexpressed, as exertion of pressure on the compressible reservoirincreases the pressure on the adhesive causing it to flow through gap 5at a rate faster than that for the same adhesive in the absence ofexerted pressure, regardless of viscosity.

A second embodiment of container-applicator is that depicted in FIG. 3.This embodiment comprises a reservoir 11 and an applicator tip 12. Thecontainer-applicator 10 can further comprise a one-time removable orbreakable sealing tip or cap as described below. In the illustratedembodiment, the adhesive flows from the reservoir 11 through a tubularextension 12 and out to the application site through an opening 13 inthe distal end of the applicator tip 14. In one preferred embodiment,the length of the extended portion 12 of the applicator tip 14 ispreferably about 0.1 to about 10 cm long, more preferably about 0.5 toabout 2 cm, but can be readily optimized in view of an intended use forthe applicator 10. The distal end may be flared, as shown, and itslargest cross-section can also come in a wide range of sizes, preferablyfrom about 0.5 to about 5 cm, generally less than about 2 cm, but it ismost preferably chosen to be larger than the width of the wound to beclosed. The configuration of the opening 13 can be a narrow ellipticalor rectangular slot or other configuration suited for the end use. Thereservoir 11 is preferably compressible or collapsible to allow forgreater control in the rate at which the adhesive is expressed from theopening 13. The reservoir may comprise any suitable material, includingmetal (such as metal foil) and plastic and combinations thereof.

In one embodiment, the distal opening 13 of the applicator tip 14 has ashape like that shown in FIG. 4. During application, the flattened sideis placed towards the skin to maximize the area of applicator-skincontact. This semi-elliptical or other concave shape of the opposingside of opening 13 results in application of a rounded strip of adhesiveas the tip 14 is drawn across the surface of the skin. Center thicknesson the order of at least about 2 times and often as much as about 3 orabout 5 times or greater the edge thickness are preferably achieved.This shape optimizes adhesive tensile strength across the top of thewound. In general the combination of thickness and inherent adhesivecharacteristics for a particular adhesive should be optimized to provideboth a sufficient bond to the skin as well as sufficient tensilestrength to resist tearing under reasonably anticipated forcesencountered by normal activities of the patient. Although this tip shapehas advantages in accordance with some embodiments, use of tips havingother shapes and configurations are contemplated, including a droppertip, tube, opening between two sheets of foil, and the like.

The applicator tip of the container-applicator can further comprise aremovable or breakable sealing tip. One embodiment of a breakablesealing tip, which can be used for a single-use device, is shown in FIG.5. The applicator cap 15 forms a solid covering for the opening of theapplicator tip (14 in FIG. 5). The applicator cap 15 is preferably ofthe same material as the applicator tip 14, the two parts meeting at abreakline 16. In one embodiment in which the tip 14 and cap 15 areintegrally formed, the breakline 16 is characterized by scoring or othermeans which weakens the junction and allows the two parts to be easilyseparated by grasping the two parts (12 and 15) in either hand andbending or tearing the pieces apart to expose the opening 13 in theapplicator tip 12 through which the adhesive is expressed. The cap 15can alternatively be press fit or threadably engaged within or over thedistal tip 14 and retained by friction as will be apparent to those ofskill in the art.

Alternatively, a single-use device can comprise a reservoir wherein theopening through which the adhesive flows is covered with a peelable orpuncturable plastic film or metal foil. In one such embodiment, the foilor film is peeled back or pierced prior to positioning the applicatorand sealing the wound. In another embodiment, the applicator portion hasa proximally extending point or projection which pierces the foil orfilm as it is threaded onto or otherwise secured to the reservoir. Asshown in FIG. 7, a certain embodiment comprises inert collapsible orcompressible metal foil tubes with long-necked applicators. Adhesivematerial is easily delivered from the tube 22 by puncturing a seal 24 ofa screw 26 on top of the container-applicator. A long-necked screw 28with a cannula 30 is positioned tightly with the screw 26 of thecontainer-applicator. The adhesive material can be expressed through anorifice of the cannula and applied evenly with a beveled length of thecannula to a desired thickness of adhesive material. The long neckapplicator can be catheter like device with orifices of 20-25 gauge and1 mm length.

One embodiment of container-applicator is a single-use, sterile woundclosure device. Preferably such a device has a pierce able or removabletip seal. The container portion of the preferred single-use woundclosure device is sized to hold preferably from about 0.2 to about 1.0grams, more preferably about 2 g of tissue adhesive, depending upon theintended use. The container can be of any of a variety of standardcontainer shapes, and is preferably compressible or collapsible so thatthe user may control the rate at which the adhesive contained therein isexpressed by varying the pressure exerted on the walls of the container.

The single-use sterile wound closure device is prepared by first takinga clean container that will serve as the reservoir and filling it withadhesive. The reservoir is then sealed. Sealing the reservoir ispreferably done by affixing an applicator tip with a removable seal tothe reservoir, or by securing a pierceable septum to the container. Thecontainer-applicator, with the adhesive sealed inside, is thensterilized by methods known to those skilled in the art which can beused on the materials from which the container-applicator is made andwhich will also not react with the adhesive.

In the alternative, the pieces which comprise the container-applicatorcan be pre-sterilized, and the device filled and sealed in a sterile orultra clean environment. This is potentially a viable method, as apreferred adhesives comprising cyanoacrylates are generally notsupportive of the growth of microorganisms.

The use of reusable coverings for applicators or applicator openings,such as caps, plugs, valves, or the like are also contemplated. Use ofthis type of covering would allow a container or container-applicator tobe used several times before it is discarded.

The containers, applicators, and container-applicators disclosed abovecan be used alone, in combination with a support structure, such as apiece of cloth, gauze or mesh, or in addition to some other securingmeans such as sutures or staples. Support structures can provide anextra measure of strength and protection for the wound, while use of aadhesive with sutures or staples can reinforce and thoroughly seal thejoint to help prevent rupture, protect the joint from abrasion, or keepit free of debris. Similarly, for a deep or penetrating wound orsurgical incision, the innermost tissues can be joined by dissolvablesutures while the exterior surface is joined using adhesives accordingto the preferred embodiments.

Closure of a wound can also be effected by the use of a devicecomprising a support structure impregnated with adhesive. In such adevice, the support structure, comprising cloth or gauze, has asufficient quantity of adhesive imbedded therein to allow for closureand sealing of a wound. Preferably, each device is individually sealedwithin air-and-water-tight packaging such as a plastic or foil pouchuntil use. Although the application and use of such a device would bevery similar to a conventional adhesive bandage, it has severaladvantages. The adhesive impregnated support structure will adhere tothe wound for a much longer time than a conventional adhesive bandageand provide a better barrier to water, dirt, and abrasion. The adhesiveimpregnated support structure would be especially suitable for use onchildren, as it would keep the wound cleaner and prevent the child fromdisturbing the wound and hampering the healing process.

Alternatively, an adhesive material according to preferred embodimentsmay be applied over an adhesive tape. The adhesive material ispreferably applied over the adhesive tape in a quantity sufficient topenetrate the tape and provide additional securement force to maintainclosure of the wound. The adhesive material covering can also aid inreducing lifting or separating of the tape from the skin and serve as abarrier to moisture or contamination.

Generally the methods of the preferred embodiments proceed by deliveringthe appropriate adhesive to the percutaneous opening. Followingapplication, the adhesive is allowed to set up. Methods of the preferredembodiments can optionally include steps of bringing the sides of thewound into opposition, applying another closure modality to be used inconjunction with the adhesive, and/or holding the surfaces togetheruntil the adhesive has adequate strength to hold the opening closed.

In a preferred embodiment, the adhesive takes on a bell-curve type shapeas shown in FIG. 6 following application. This shape is advantageous inthat it places the thickest part of the layer, and thus the strongestpart of the layer, over the opening in the skin to provide enhancedresistance to tearing, rupture, or other stress or damage to the openingfollowing closure. The added protection provided by a thicker layer canaid in speeding the healing process and allowing for a minimum ofstretching of the wound as it heals, which may help minimize scarring.The adhesive can be applied such that the thickness over thepercutaneous opening is at least about 0.1 mm, often from about 0.5 mmto about 4 mm thick, or from about 1.0 to about 2.5 mm thick.

In one embodiment, an adhesive is used for which the polymerizationprocess of the adhesive is enhanced by the presence of water or a basicsubstance. Prior to application of the adhesive, water is optionallyplaced on the skin in the general area of the wound or opening,including a spraying or misting water or saline on the area, or wipingthe area with an alcohol/water prep pad. The water which remains on thesurface may increase the rate at which the adhesive sets up on thewound. However, it should be noted that in some cases the presence ofadditional water may impair crosslinking and the polymerization andeventual tensile strength of the adhesive.

Initiators, cross-linkers, catalysts, and other compounds which aid anadhesive in setting up can be applied in a similar manner, provided thatthey would not irritate the open wound, or cause other undesirable sideeffects.

When applying adhesive of the preferred embodiments, the surfaces of thewound, laceration, percutaneous incision, or the like intended forclosure are brought in contact with each other by use of the fingers,forceps, or a similar device. A sufficient amount of adhesive isdelivered to the surface so that proper sealing and closure retentionwill occur. When sealing the joint formed by the sides of the wound,laceration, or percutaneous incision, the adhesive is applied to theexterior surface of the wound and allowed to polymerize so that it formsa film over the entire wound. Preferably, adhesives are applied in amanner to minimize the amount of adhesive which seeps between the edgesof a wound. The amount of adhesive to apply in any given case, and thusthe area and thickness of the resulting film, can depend on severalfactors including placement of the wound on the body, depth of thewound, tissue sensitivity to the adhesive, and the like. Adhesive can beapplied alone or in combination with a support structure or othersecuring means such as sutures. Through routine experimentation,however, one of skill in the art will be able to exercise clinicaljudgment to determine an appropriate quantity of adhesive to provideeffective closure for a particular procedure.

Methods of the preferred embodiments are preferably directed towardclosing and sealing a wound by sealing and securing together adjacenttissues, such as opposing pieces of skin, in a patient. The need forclosure of such a wound can arise during surgical procedures, as aresult of percutaneous incision. The need can also arise as a result oftraumatic injury resulting in a laceration or other wound which breaksthe skin.

Generally, a method of closing a wound, laceration, percutaneousincision, or the like proceeds by first assessing what type of closureor combination of closures is proper for a wound given factors such asthe size, depth, and location of the wound as well as an assessment ofthe overall needs and requirements of the patient. Such assessments areroutinely done by those skilled in the medical arts. In a non-clinicalsetting, the assessment step will likely be much more cursory.

Next, a suitable formulation of adhesive, an applicator, and a method ofapplication are chosen. These three choices are somewhat interconnected,as the choice of a particular applicator constrains the method ofapplication, and a particular formulation of adhesive can constrain thetype of applicator or method of application which can be used, andvice-versa.

The choice of a suitable formulation of wound closure adhesive, asdisclosed herein, can depend upon characteristics of a adhesive such asits viscosity, biodegradability and rate thereof, resulting tensilestrength upon polymerization, flexibility when polymerized,histotoxicity, and polymerization rate. Specific characteristics can bedesired to fit clinical needs as dictated by factors such as the size ofthe wound, the amount and rate of bleeding from the wound, the locationof the wound on the body, and potential stress on the sealed wound.

The choice of applicator and method of application can, in part, bedetermined by factors such as the composition, viscosity, andpolymerization time of the adhesive, and the geometry, size andplacement of the application site. Such a choice can also be constrainedby the tools and devices available to the user. Examples of preferredapplicators are disclosed above and examples of preferred methods ofapplication are described below.

Next, the wound may need to be prepared before closure. Activitiesinvolved in wound preparation are highly situational, but are routinelydone by those skilled in medicine, nursing, and related arts. Woundpreparation can involve tasks, such as removal of debris, dirt, oil, orexcess tissue from the wound, application of pressure or similarmeasures to bring about the cessation of bleeding, cleansing the wound,application of an antimicrobial preparation, use of additional closuremeans such as sutures, and other such tasks. In a non-clinical setting,the patient or use can also perform some of these same tasks.

If the surfaces of the wound naturally pull apart, it can beadvantageous to bring the two surfaces into contact with each other andalign them by use of the fingers, support structure, forceps or othersuitable medical instrument. In such a case, the two surfaces arepreferably held together as the adhesive is applied and afterwards untilsufficient polymerization has taken place to allow the closure to beself-supporting. Alternatively, the two surfaces can be brought togetherby sutures, staples, tape or other securing means and then furthersealed by application of a chosen adhesive. Such methods can allow foreventual scarring of the opening to be minimized. In wounds for whichthe skin is not separated, this step can be skipped.

The chosen adhesive is then applied using the applicator and methodchosen in an earlier step. The entirety of adhesive application ispreferably done within a limited period of time, as the strength of theclosure formed by two or more successive applications of adhesive(wherein one application has been allowed to polymerize before the nextapplication) may not be as strong as the closure formed by oneapplication allowed to polymerize to form a single layer on the skinsurface. Adhesive is applied in a quantity sufficient to effect woundclosure and sealing. More can be applied, if desired, to increase thestrength of the closure as discussed above, or likewise a supportstructure may be applied. Determination of quantity of adhesive appliedcan be determined by routine experimentation and exercise of clinicaljudgment. Specific methods of application involving the use ofcontainer-applicators are discussed in the paragraphs which follow.

One specific method of application is that involving the use of therollerball container-applicator pictured in FIG. 1. To use thiscontainer-applicator, first any sealing means is removed or broken.Then, as depicted in FIG. 2, the container is tipped so that therollerball is pointing in a generally downward direction and the bottomof the reservoir portion is pointing in a generally upward direction.Such orientation of the container-applicator facilitates the flow ofadhesive towards the rollerball applicator portion through which it canthen be applied to the wound. Preferably the adhesive is applied bymoving the container-applicator back and forth over the surface of thewound and surrounding skin areas while keeping the rollerball in contactwith the wound at all times. Although a back and forth movement ispreferred, any movement of the applicator which serves to deliver theadhesive to the intended site without disturbing the wound itself iscontemplated.

If the reservoir portion of the container-applicator is compressible orcollapsible, the rolling of the applicator over the surface of the skincan be accompanied by squeezing or otherwise compressing the walls ofthe reservoir. With such a collapsible or compressible reservoir, therate of flow of adhesive and therefore the amount of adhesive delivered,is proportional to the amount of pressure applied to the walls of thereservoir. The quantity and rate of adhesive delivery can thus becontrolled by the user.

Another specific method of application is that using acontainer-applicator of the type depicted in FIG. 3. To apply adhesive,first any sealing means such as a foil seal, peel-away thin film orbreakable tip is punctured or removed to allow for flow of adhesive. Theapplicator tip is preferably placed on or slightly above the surface ofthe wound to be sealed. If a semi-elliptical tip is used, such as thatpictured in FIG. 4, the flattened side is preferably placed closest tothe skin. The adhesive is then allowed to flow through the applicatorand onto the surface of the skin forming a profile such as shown in FIG.6. Preferably, the reservoir portion comprises collapsible orcompressible walls such that the user may exert pressure on the walls tofacilitate the delivery of adhesive to the skin, and thus control therate at which the adhesive is expressed from the applicator tip. The tipis moved over the surface of the skin, following the contours of thewound, resulting in the deposition of a strip of adhesive on the skincovering the wound. Additional strips may be laid down in a similarmanner to thicken or expand the area of adhesive coverage.

In accordance with another embodiment, the reservoir is provided as aseparate component from the applicator tip. In this embodiment, thereservoir is provided with a pierceable seal or septum, such that a unitvolume of adhesive can be sealed within the reservoir. Pierceableseptums or seals comprising silicone, other polymeric materials known inthe medical industry, as well as metal foils or thin polymeric films maybe utilized, as will be apparent to those of skill in the art in view ofthe nature of the complimentary piercing structure on the applicatortip.

The detachable applicator tip comprises an applicator surface on adistal side thereof, and a cannula, needle or other piercing structureprojecting proximally from a proximal side thereof A retention structureis preferably also provided, for securing the applicator tip to thereservoir. In one embodiment, the retention structure is an axiallyextending annular flange having a thread on the radially inwardly oroutwardly facing surface thereof, for threadably engaging the top of thereservoir. Any of a variety of other retention structures can beutilized, as will be apparent in view of the disclosure herein.

Prior to use at the clinical site, the applicator tip is secured to thereservoir such that the proximally extending piercing member on theproximal side of the applicator tip pierces the septum or other seal onthe reservoir, thereby placing the contents of the reservoir in fluidcommunication with the distal applicator surface. This embodiment isparticularly suited for a one-time use disposable device. The applicatorsurface can be of any of a variety of structures disclosed elsewhereherein, such as a rollerball, or a specially configured opening such asa slot, for expressing a thin layer of sealing adhesive over the surfaceof the tissue on either side of a wound.

Any of the foregoing methods can be combined with the application of asupport structure, such as gauze. A layer of adhesive is first appliedto the wound, onto which gauze or other support structure is affixed,the adhesive acting to secure the gauze in place. More adhesive may thenbe applied over the gauze to further secure it and strengthen theclosure. In the alternative, gauze can be first placed over the woundand then covered and secured to the wound by subsequent application(s)of adhesive as described above. In either case, alternate layers ofadhesive and gauze may be applied to form a flexible, reinforcedstructure which effects closure of the wound and sealing.

As an alternative to the method discussed above, a prepackaged adhesiveimpregnated support structure can be applied to the wound to achieveclosure. Such a device, as described above, is preferably packaged in asealed pouch and comprises a support structure, such as a section ofcloth, that is saturated with a quantity of adhesive sufficient to allowfor attachment of the support structure and effect closure of a wound orsection of a wound of a size corresponding to the size of the supportstructure. Closure of a wound using such a device is somewhat comparableto using a common adhesive bandage and is particularly well-suited fornon-clinical use. First, the pouch containing the device is opened andthe device removed therefrom. The device is then placed over the surfaceof the wound and then pressed into place to ensure good contact betweenthe device and the skin. If additional coverage is required or desired,additional devices may be applied. When more than one device is used,they are preferably applied within a short time of each other so thatthey polymerize at nearly the same time.

The various methods and techniques described above provide a number ofways to carry out the invention. Of course, it is to be understood thatnot necessarily all objectives or advantages described may be achievedin accordance with any particular embodiment described herein. Thus, forexample, those skilled in the art will recognize that the methods may beperformed in a manner that achieves or optimizes one advantage or groupof advantages as taught herein without necessarily achieving otherobjectives or advantages as may be taught or suggested herein.

Furthermore, the skilled artisan will recognize the interchangeabilityof various features from different embodiments. Similarly, the variousfeatures and steps discussed above, as well as other known equivalentsfor each such feature or step, can be mixed and matched by one ofordinary skill in this art to perform methods in accordance withprinciples described herein.

Although the invention has been disclosed in the context of certainembodiments and examples, it will be understood by those skilled in theart that the invention extends beyond the specifically disclosedembodiments to other alternative embodiments and/or uses and obviousmodifications and equivalents thereof. Accordingly, the invention is notintended to be limited by the specific disclosures of preferredembodiments herein, but instead by reference to claims attached hereto.

1. A method of closing a percutaneous opening, having a first dermalsurface on a first side of the opening and a second dermal surface on asecond side of the opening and. generally coplanar with the first dermalsurface, the method comprising the step of: applying an adhesive layeracross at least a portion of the first and second dermal surfaces andspanning the opening, wherein the adhesive comprises one or morecyanoacrylate monomers, cyanoacrylate polymer, and plasticizer; andwherein the adhesive exhibits a sufficient viscosity to substantiallyprevent flow of the adhesive into the opening.
 2. A method as in claim1, wherein the viscosity is within the range of from about 100 to about50,000 centipoise.
 3. A method as in claim 1, wherein the viscosity iswithin the range of from about 100 to about 5,000 centipoise.
 4. Amethod as in claim 1, wherein the viscosity is at least about 100centipoise.
 5. A method as in claim 1, wherein the adhesive comprisesabout 70-95% cyanoacrylate monomer, about 1-15% cyanoacrylate polymer,and about 2-15% plasticizer.
 6. A method as in claim 5, wherein theadhesive comprises about 80-90% cyanoacrylate monomer, about 5-10%cyanoacrylate polymer, and about 5-10% plasticizer.
 7. A method as inclaim 1, wherein the cyanoacrylate monomer comprises a mixture ofoctylcyanoacrylate and butylcyanoacrylate.
 8. A method as in claim 7,wherein the cyanoacrylate monomer comprises about 60% to about 80%octylcyanoacrylate and about 20% to about 40% butylcyanoacrylate.
 9. Amethod as in claim 7, wherein the cyanoacrylate monomer comprises about65% to about 75% octylcyanoacrylate and about 25% to about 35%butylcyanoacrylate.
 10. A method as in claim 1, wherein thecyanoacrylate polymer comprises poly(octylcyanoacrylate).
 11. A methodas in claim 1, wherein the plasticizer is tributyl citrate.
 12. A methodas in claim 1, wherein the adhesive layer has a thickness over theopening of at least 1 millimeter.
 13. A method of closing ad sealing ajoint formed between a tissue of a patient and a second surface,comprising: positioning a tissue of a patient adjacent to a secondsurface; securing the tissue to the second surface using a primaryclosure modality to form a joint; delivering an adhesive comprisingcyanoacrylate monomer, cyanoacrylate polymer, and a plasticizer to thejoint; and permitting the adhesive to polymerize.
 14. A method as inclaim 13, wherein the second surface is an autologous tissue, allographtissue, animal tissue, biologically compatible metal, polymericmaterial, or prosthetic device.
 15. A method as in claim 13, wherein theprimary closure modality is sutures or staples.
 16. A method as in claim13, wherein the tissue and the second surface are adjacent surfaces ofthe skin of a patient.
 17. A method of closing and sealing a wound in apatient, comprising the steps of: identifying a percutaneous woundhaving first and second sides; delivering a layer of wound closureadhesive comprising one or more cyanoacrylate monomers, cyanoacrylatepolymer, and plasticizer to the surface of skin on each of the first andsecond sides and across the wound in a quantity sufficient to retainclosure and sealing of said wound; and restraining adhesive fromentering the wound.
 18. A method as in claim 17, wherein the restrainingstep comprises providing the wound closure adhesive with a sufficientviscosity to extend in a layer across the wound, while substantiallypreventing the adhesive from entering the wound.
 19. A method as inclaim 18, wherein the viscosity is at least 100 centipoise.
 20. A methodof covering a trauma to an outer layer of a skin in a patientcomprising: delivering an adhesive comprising cyanoacrylate monomer,cyanoacrylate polymer, and a plasticizer to a surface of the skincovering an area of the trauma to the outer layer of the skin in aquantity sufficient to cover said trauma; and permitting the adhesive topolymerize.
 21. A method as in claim 20, further comprising applying anaqueous solution to the trauma prior to delivering the adhesive.
 22. Amethod as in claim 20, wherein the adhesive has a prepolymerizationviscosity of at least about 100 centipoise.
 23. A method as in claim 20,wherein the trauma is selected from the group consisting of abrasions,scrapes, burns, blisters, bedsores, ulcers, chapping, and chafing.